Ticks, flukes, and genomics: Emerging pathogens revealed

Ehrlichiosis is no star of science. This emerging disease has an awkward name, vague flu-like symptoms, and a nasty habit of being caused by bacteria that live inside ticks and flatworms. But in the current issue of the journal Public Library of Science Genetics (PLoS Genetics), scientists put ehrlichiosis under the genomic spotlight-and discover some brilliant biology.

Led by scientists at The Institute for Genomic Research (TIGR) and The Ohio State University (OSU), a team of researchers report the complete genomes of three emerging pathogens that cause ehrlichiosis-Anaplasma phagocytophilum, Ehrlichia chaffeensis, and Neorickettsia sennetsu-and compare the genomes with those of 16 other bacteria with similar lifestyles. The study reports new genes that allow the bacteria to evade a host's immune system, adapt to new niches, and more. Finally, the report reconstructs the metabolic potential of five representative genomes from these bacteria.

"By comparing so many different pathogens, some closely related and others diverse, we're able to identify genes linked to different diseases and organisms," explains molecular biologist Julie Dunning Hotopp of TIGR, first author of the PLoS Genetics paper. Because the pathogens causing ehrlichiosis are obligate intracellular bacteria-able to thrive only inside host cells-they are hard to isolate and study in the lab, Hotopp adds. "How are these diseases different? How are they the same? Can we correlate certain genes with certain characteristics? For the first time, our comparative genomics database offers a resource for tackling these questions."

Recognized since at least the 1930s, ehrlichiosis sickens not only humans, but also dogs, cattle, sheep, and other animals. In Japan, human ehrlichiosis is commonly called sennetsu fever. In the U.S., most human cases have been linked to ticks.

In the new study, scientists uncovered a clue to how ehrlichiosis-causing bacteria infect such diverse animals. One of the three primary bacteria sequenced, A. phagocytophilum, contains roughly 1,400 genes-including more than 100 variations of a single gene that codes for a protein allowing the bacteria to evade the immune system of the organism it has infected. This protein sits on the bacteria's outer membrane surface. When the bacteria, through tick bites, transfers to a human, say, or horse, the bacteria chooses the protein variation needed to stay hidden from that particular host.

"These genome sequences have revolutionized the types of experiments [scientists] can perform to understand these diseases," says microbiologist Yasuko Rikihisa of OSU's College of Veterinary Medicine. "Already, at least four labs are performing, or planning to perform, whole genome DNA microarray analysis and proteomic analysis of these bacteria."

In addition to comparing genomes, the current study used those genomes to reconstruct the metabolic potential (the ability to use and produce energy and compounds) of five bacteria, representing the numerous organisms compared. With this final analysis, they gleaned new insight into the broader tactics used by different bacteria. Ehrlichiosis pathogens, for instance, appear capable of making vitamins that a host tick lacks in its regular diet.

"This study is a beautiful example of how in-depth comparative genomics can lead to the identification of molecular features that underlie the lifestyle of pathogens," says TIGR molecular biologist Hervé Tettelin, senior author of the PLoS Genetics article. "We could not have reached these conclusions by independently studying the genome sequence of each individual pathogen," he adds. "Now we know how some of the pathogens studied infect or provide benefits to their hosts."

The scientists hope to build on this work, with potential studies to determine which bacterial genes are turned on during ehrlichiosis infection and to track the evolutionary differences between ehrlichiosis-causing organisms in different parts of the world. Other scientists can build on the new work as well, by accessing the comparative database now online at http://www.tigr.org/sybil/rcd/. This genome sequencing project work was funded by the National Institutes of Health.